EP0368994B1 - Benzothiazepine zur Herstellung von Medikamenten zur Milderung von epileptischen Anfällen - Google Patents

Benzothiazepine zur Herstellung von Medikamenten zur Milderung von epileptischen Anfällen Download PDF

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EP0368994B1
EP0368994B1 EP89906896A EP89906896A EP0368994B1 EP 0368994 B1 EP0368994 B1 EP 0368994B1 EP 89906896 A EP89906896 A EP 89906896A EP 89906896 A EP89906896 A EP 89906896A EP 0368994 B1 EP0368994 B1 EP 0368994B1
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diltiazem
seizures
straight chain
acetyloxy
branched alkyl
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EP0368994A1 (de
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Ray Howard Zobrist
William Ray Morrone
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Aventis Pharmaceuticals Inc
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Marion Merrell Dow Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis

Definitions

  • the invention relates the use of a benzothiazepine calcium channel antagonist in the manufacture of a medicament for use in the treatment of generalized tonic-clonic type seizures associated with epilepsy in mammals.
  • Abnormal electrical discharges can arise in the brain due to various electrical or chemical stimuli. Certain regions of the brain including the temporal lobe and the deep nuclear aggregates of the motor cortex, the amygdala and the hippocampal structures of the limbic system are particularly sensitive to abnormal electrical discharges. An alteration in membrane permeability to extracellular calcium appears to be a critical event in the genesis of these abnormal electrical discharges and probably precedes paroxysmal neuronal discharge associated with epileptic seizures.
  • Epilepsy is a collective designation for a group of central nervous system disorders having in common the spontaneous occurrence of seizures associated with the disturbance or loss of consciousness, These seizures are usually, but not always, associated with characteristic body movements (convulsions) and sometimes autonomic hyperactivity. Seizure in epilepsy detonation is believed to originate in the non-specific subcortical mesodiencephalic reticular systems and diffuse bilaterally into the cerebral cortex.
  • the motor cortex, the amygdala and the hippocampus have a low threshold and high susceptibility to seizure possibly due to the vulnerability of their vasculature to compression and biochemical disturbances. See , e.g. , Glaser, "The Epilepsies," Textbook of Medicine , Beeson and McDermott, eds., WB Saunders Co., Philadelphia, 1975, pp. 723-24.
  • Epileptic seizures are divided into partial and generalized seizures on the basis of the clinical manifestations of the attacks and the electroencephalographic (EEG) pattern. Each of these two general epileptic categories is then further subdivided into three or more subcategories depending on the classification scheme employed as shown in Table I. Accurate diagnosis is therefore essential since pharmacotherapy is highly selective for a particular type of epileptic seizure.
  • Ca2+ free intracellular calcium ion
  • Changes in free intracellular calcium ion (Ca2+) levels provide a signal allowing muscle and nerve cells to respond to a variety of external stimuli.
  • neurotransmitter release is specifically dependent on Ca2+ entry into neurons.
  • Membrane permeability to extracellular Ca2+ may also be a factor preceding neuronal discharge and seizure appearance.
  • Recent studies have now suggested that the flux of extracellular Ca2+ into neurons may be directly related to the development of epileptic seizures. See , e.g. , Pumain et al ., Science 222 :177-179, 1983; Schwartzkroin et al ., Ann. Neurol. 7 :95-107, 1980.
  • the inhibition of Ca2+ flux in neurons by phenytoin may be through its binding to Ca2+ channel regulatory proteins, since phenytoin has been shown to inhibit the binding of nitrendipine, a known Ca2+ channel antagonist, to neuronal membranes. See , e.g. , Harris et al ., Biochem. Pharmacol. 34 :2187-2191, 1985.
  • Ca2+ channels which are proteins that span the cell membrane to provide an aqueous route for passage of ions into cells. See e.g. , Greenberg, Ann. Neurol. 21 :317-330, 1987, for a review. Ca2+ flux through Ca2+ channels is believed to be a passive process merely requiring that the channels be open to permit Ca2+ ions to descend an electrochemical gradient into the cells.
  • Two broad classes of Ca2+ channels are known: (1) Voltage-dependent Ca2+ channels activated to open by membrane depolarization and (2) so-called receptor-operated Ca2+ channels, which open as a result of ligand-binding to specific cell-surface receptors.
  • Ca2+ channel heterogeneity exists, based on differences in membrane potentials required to open the channels, tendency to inactivate and pharmacologic sensitivity.
  • a subpopulation of Ca2+ channels in neurons of the central nervous system (CNS) appear to be pharmacologically distinct from Ca2+ channels found in peripheral tissues. See e.g. , Scriabine et al ., in New Drugs Annual , ed. A. Scriabine, Raven Press, New York, pp. 197-218, 1985.
  • Ca2+ channel antagonists The flux of Ca2+ ions through Ca2+ channels can be inhibited by a diverse group of organic compounds termed Ca2+ channel antagonists.
  • Ca2+ channel antagonists Four chemical classes of Ca2+ channel antagonists have been generally recognized: (1) the dihydropyridines, exemplified by nifedipine and nimodipine; (2) the phenylalkylamines, such as verapamil; (3) the benzothiazepines, such as diltiazem; and (4) the diphenylalkylamines, such as flunarazine.
  • Ca2+ channel antagonists show a high degree of specificity, both structurally and sterically. Many Ca2+ channel antagonists are highly stereospecific, in that one of two optical isomers can be substantially more potent than the other. Furthermore, it has been shown that minor structural alterations can change a Ca2+ channel antagonist into a Ca2+ channel activator which actually enhances Ca2+ influx. For example, it has been shown with certain dihydropyridine compounds that one isomer can block Ca2+ influx while the other isomer stimulates Ca2+ flux. See , e.g. , Franckowiak et al ., Eur. J. Pharmacol. 114 :223-226, 1985; Kongsamut et al ., Biochem. Biophys.
  • Ca2+ channel antagonists have been therapeutically categorized as vasodilators and have found wide clinical use in treatment of cardiovascular problems, such as angina, and hypertension. Because of the suggested relationship between Ca2+ influx into neurons and the development of epileptic seizures, it is believed that inhibition of Ca2+ flux by Ca2+ channel antagonists may be therapeutically useful, either alone or as adjuvants to traditional anticonvulsant drugs, in treating epileptic seizures.
  • Ca2+ channel antagonists by themselves, possess no anticonvulsant activity.
  • the d, d1 and 1-cis isomers of diltiazem were shown to have no anti-chemoshock or anti-electroshock activity, even at doses of 200 mg/kg, p.o. See , e.g. , Nago et al ., Japanese J. Pharmacol. 2:467-478, 1912.
  • Ca2+ channel antagonists per se e.g., cinnarizine nifedipine, nimodipine, diltiazem and verapamil, had no anti-epileptic activity in mice as measured with the maximal electroshock test. See , e.g. , Fisher et al ., Pharmazie 42 :420-421, 1987.
  • Ca2+ channel antagonists may augment the effects of traditional anticonvulsant agents. See , e.g. , Shelton et al ., Brain Res. 402 :399-402, 1987. There is some evidence in animal epileptic model systems and in minimal clinical studies that specific dihydropyridine and diphenylalkylamine Ca2+ channel antagonists, especially those with CNS-selectivity, may be effective antiepileptic agents, particularly if such agents are used as adjuvant therapy to known anticonvulsant drugs. See e.g. , Greenberg, supra ; Speckman et al ., Funct. Neurol.
  • Ca2+ channel antagonists may have anticonvulsant activity is especially important since the currently available antiepileptic drugs are not only ineffective in many patients, but can frequently cause side effects ranging in severity from minimal CNS impairment to, in rare cases, death due to aplastic anemia or hepatic failure. Furthermore, administration of certain antiepileptic drugs, e.g. , phenytoin, to pregnant epileptic women may result in the production of birth defects in the children, i.e. , the so-called "Dilantin syndrome.” On the other hand, Ca2+ channel antagonists, as a class of drugs, have been shown to possess minimal neurolgogical and physiological side effects. See , e.g. , Chaffman et al ., Drugs 29 :387-454, 1985. Thus, Ca2+ channel antagonists, especially those with CNS-selectivity, may be useful antiepileptic drugs.
  • the present invention provides the use of a compound having the formula: wherein X is hydrogen, a straight chain or branched alkyl of up to 8 carbon atoms, hydroxy, a halogen or a straight chain or branched alkyl halide of up to 8 carbon atoms; Y is a straight chain or branched alkylene of up to 8 carbon atoms; R1 is hydrogen, hydroxy or acetyloxy; R2 and R3 are each a straight chain or branched alkyl of up to 8 carbon atoms or a non-aromatic saturated or unsaturated cycloalkyl having no more than 6 carbon atoms or together are a heterocyclic, and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in the treatment of generalized tonic-clonic type epileptic seizures in mammals.
  • heterocyclic is meant a single ring, preferably saturated, having no more than 6 carbon atoms.
  • the compound of formula I may be systemically administered to the mammal orally or by injection. Effective amounts will range from 0.5 to 360 mg of the benzothiazipine compound (I) administered per day.
  • Most preferred compounds for use in the invention include (+)(2S,3S)-3-acetyloxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one (herein, diltiazem) and (+)(2S,3S)-3-acetyloxy-8-chloro-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one (herein designated TA-3090).
  • Fig. 1 is a graph showing protection from MES-induced seizures after intraperitoneal administration of benzothiazepine compounds.
  • Fig. 2 shows the time course for protection against MES-induced seizures following oral administration of benzothiazepine compounds.
  • Fig. 3 is a bar graph showing protection from MES-induced seizures after oral administration of benzothiazepine compounds.
  • Fig. 4 is a graph showing protection from MES-induced seizures after administration of benzothiazepine compounds and metabolites thereof.
  • the compound of formula I is a benzothiazepine calcium channel antagonist which selectively inhibits the influx of Ca2+ ions into neurons of the central nervous system (CNS).
  • Y is ethyl
  • X is hydrogen or chloro, preferably hydrogen or 8-chloro
  • R1 is acetyloxy
  • R2 and R3 are each a lower alkyl, most preferably methyl.
  • Most preferred compounds for use in the practice of the invention include diltiazem in which Y is ethyl, X is hydrogen, R1 is acetyloxy, and R2 and R3 are each methyl and TA-3090 in which Y is ethyl, X is 8-chloro, R1 is acetyloxy, and R2 and R3 are each methyl.
  • Most preferred forms of these compounds for use in the invention include the hydrochloride salt of diltiazem and the maleate salt of TA-3090.
  • certain metabolites of diltiazem e.g. , desacetyldiltiazem (herein designated M1) which results from the oxidative deacetylation at position 3 (R1) of diltiazem, are also active and useful in the invention.
  • Diltiazem and TA-3090 surprisingly have proven effective in ameliorating or preventing seizures in the maximal electroshock convulsion (MES) test in mice.
  • the MES test is recognized as a model for generalized tonic-clonic type epileptic seizures and drugs which are effective in the MES test are usually clinically effective in treating such epileptic forms. See , e.g. , Swinyard et al ., ISI Atlas of Pharmacology, in press, 1988.
  • TEE tonic hind limb extensions
  • death in the MES indicates a lack of protection against generalized tonic-clonic type epileptic seizures.
  • Diltiazem and TA-3090 were both effective in protecting mice against the appearance of THE and/or death in the MES test after both oral and intraperitoneal administration. The results were surprising in that diltiazem and TA-3090 are not known to enter the central nervous system in quantities sufficient to produce pharmacologic activity. In concurrent testing, verapamil, which is not CNS-specific, afforded relatively little protection in the MES tests. Furthermore, previous studies have shown that, in contrast to diltiazem and TA-3090, oral administration of the CNS-selective dihydropyridine calcium channel antagonist nimodipine was ineffective against MES-induced seizures but protected against pentylenetetrazole-induced seizures (a model for absence seizures). See , e.g. , Hoffmeister et al ., Arzneiffenbachforschung 32 :347-360, 1982.
  • the invention is thus particularly directed to treating generalized tonic-clonic type epileptic seizures. Since benzothiazepine Ca2+ channel blockers have been rarely reported to produce adverse side effects during normal usage, it is believed that the invention will afford a high level of seizure control in mammals, without the toxic side effects often produced by known anticonvulsant drugs used to treat epileptic seizures.
  • the medicament of the present invention may be systemically administered orally or by injection.
  • Total unit daily dosages or therapeutically effective quantities can vary over a wide range, for instance, from about 0.5 to about 360 mg per day depending on the factors provided below.
  • a suitable total daily dose of the benzothiazapine compound (I) or pharmaceutically acceptable salt thereof preferably varies from about 30 to 180 mg per day, preferably divided into several dozes.
  • the total unit daily dosage of the benzothiazepine (I) compound is administered to the patient in three to four equally divided daily doses. Accordingly, when the medicament is orally administered it is preferably administered in a divided dose form given 3 to 4 times daily to provide a total dose of 0.5 to 360mg per day.
  • Other conditions which may affect the amount of compound to be administered include the severity of the epileptic condition, whether generalized tonic-clonic type epileptiforms are present, the age, sex and general physical condition of the patient, and whether the benzothiazepine compound (I) will be used in conjunction with a known anticonvulsant drug, such as phenytoin or phenobarbital.
  • the benzothiazepine compounds (I) may be administered in the form of pharmaceutical preparations containing the compounds admixed with pharmaceutically acceptable carriers suitable for parenteral or oral administration. preferably the compounds will be orally administered as tablets, capsules, powers or in liquid form such as suspensions, solutions, emulsions or syrups.
  • conventional excipients e.g. , sodium citrate, lactose, microcrystalline cellulose, starch
  • lubricating agents e.g. , anhydrous silicic acid, hydrized castor oil, magnesium stearate, sodium lauryl sulfate, talc
  • binding agents e.g.
  • each unit dosage form of the active ingredient can contain from about 5 to 95% of the same by weight based on the entire composition with the remainder comprising conventional pharmaceutical carriers.
  • the therapeutic agent is used as an aqueous solution, i.e. , injection, the solution may contain from about 0.05 to 5.0% of same by weight based on the entire solution.
  • Diltiazem which is widely used to treat cardiovascular problems, including hypertension, may be readily obtained from commercial sources, e.g. , Marion Labs, for use in the invention or prepared according to the method disclosed in U.S.P. 4,438,035.
  • diltiazem preferably in its hydrochloride form, is admixed with a pharmaceutically acceptable carrier and administered to a mammal who suffers from such seizures and is in need of treatment.
  • Diltiazem may be formulated for administration orally or by injection as indicated above.
  • patients will be maintained on oral total daily dosages of about 0.5 to 360 mg, preferably about 30 to 180 mg per day, in divided doses to ameliorate or prevent epileptic seizures.
  • the preferred route is by injection. Effective i.v. dosage amounts of the compound will be lower than those for oral administration. It is well within the skill of the treating physician to determine the amount of the compound which will ameliorate seizures in a given patient.
  • Diltiazem preferably in the hydrochloride form, has been shown to be effective in protecting against generalized tonic-clonic type epileptic seizures in an animal model of epilepsy when administered in a single undivided dose orally or by peritoneal injection, in an amount ranging from about 0.3 to 200 mg per kg body weight.
  • the most effective dose range in the mouse model appeared to be about 50 to 200 mg per kg of body weight.
  • a dose of about 200 mg per kg body weight has been shown to afford excellent protection against experimentally induced tonic-clonic seizures. Maximal protection against these seizures appears to be about 60 minutes following oral administration of diltiazem, with a time range of protection between about 15-300 minutes.
  • the benzothiazepine Ca2+ channel antagonist used in the present invention is the compound TA-3090, preferably administered as a maleate salt.
  • the considerations for the particular formulation, route of administration of TA-3090 and determining the therapeutically effective amount of the compound are the same as for diltiazem. In general, the therapeutically effective amount of TA-3090 will be lower than that of diltiazem.
  • Oral administration of about 30 mg per kg body weight of TA-3090 also provided very good protection against experimentally-produced generalized tonic-clonic type epileptic seizures. Maximum protection following oral administration of TA-3090 was seen at about 60 minutes following oral drug administration, with good protection until about 180 minutes post-administation. TA-3090 affords some protection as early as 15 minutes and as long as 300 minutes following oral administration.
  • benzothiazepine compounds (I) of the invention not only will be useful in the treatment of generalized tonic-clonic type epileptic seizures with the aforementined reduction in side effects, but also may prove useful in providing treatment of certain individuals suffering from epileptic seizures for whom treatment has heretofore proved ineffective.
  • the calcium channel antagonists diltiazem, TA-3090, and verapamil were tested to determine their efficacy following intraperitoneal injection in inhibiting artificially induced convulsive episodes in two models of epilepsy, i.e. , the MES test and the maximal Metrazol (pentylenetetrazole) convulsion (MMC) test in mice.
  • the known anticonvulsant agents phenytoin and valproic acid were used in the MES and MMC tests, respectively, as positive controls.
  • mice Male Swiss-Webster mice (20-30 gm) were randomly divided into 5 groups, weighed, and treated as follows:
  • MAXIMAL METROZOL CONVULSION TEST MMC: Each test compound was administered as indicated above. Twenty minutes later, Metrazol (pentylenetetrazole, 85 mg/kg) was subcutaneously administered to each animal. The animal was then observed for an additional 30 minutes for the absence or incidence of forelimb clonic convulsions. Clonic convulsive episodes of 5 seconds or more duration were considered lack of protection.
  • mice were immediately sacrificed by cervical dislocation either 10 seconds after the appearance of convulsions or 30 minutes post-Metrazol or electroshock administration, whichever came first. Protection against convulsions was recorded as a quantal (all or none) response.
  • ED50 the dose at which 50% of the animals were protected
  • seven half-logarithmetically-spaced doses of the test compounds were administered to groups of 10-20 animals. The ED50 dose was obtained by probit analysis.
  • Fig. 1 is a bar graph showing the relative protective activities of the various test compounds against electroshock-induced seizures in the mouse. The number above each bar represents the percentage of animals protected against tonic seizures.
  • TA-3090 afforded 90% protection at a dose of about 10 mg/kg body weight. Unexpectedly, however, no protection was seen at the next higher dose of 30 mg/kg. Equally unexpected was the added observation that nine of the ten animals in this unprotected 30 mg/kg group also died within a matter of 5-15 seconds after shock administration.
  • Verapamil while showing some degree of antiseizure activity between 1 and 30 mg/kg, was never able to afford greater than 35% protection in the MES test. At a verapamil dose of 100 mg/kg all animals died prior to MES testing within 5-10 minutes of drug administration.
  • Drugs which are effective in the MES test usually are effective in the treatment of generalized tonic-clonic and cortical focal convulsions, while compounds effective in the MMC test are generally effective in preventing absence-type seizures.
  • this example demonstrates that the benzothiazepine Ca2+ channel blockers diltiazem and TA-3090 possess anticonvulsant actions against certain epileptiforms, e.g. , generalized tonic-clonic type epileptic seizures (Table II).
  • diltiazem and TA-3090 appear to be at least equal to phenytoin in efficacy in the prevention of generalized tonic-clonic type seizures.
  • This Example shows the time of maximal protection against the appearance of tonic-clonic type epileptic seizures in the MES model of epilepsy following oral administration of diltiazem and TA-3090.
  • the test system and amounts of drug administered were as follows:
  • mice Male Swiss Webster mice weighing 20-30 grams as in Example 1 were obtained from Sasco Inc. (Omaha, Iowa). Animals were housed 5 to a cage for at least one week prior to the study with food and water ad libitum. Mice were randomly divided into 4 groups, weighed, and treated as follows:
  • the MES tests were carried out as follows: Each drug was orally administered to the mice as indicated above. At the specified time after oral drug administration (15, 30, 60, 90, 120, 180, and 300 minutes), a maximal electroshock (MES)-induced seizure was generated in the mouse by the corneal application of a 40 mA electrical current for 0.2 seconds, as in Example 1. The appearance of tonic hindlimb extensions (THE) exceeding a 90 degree angle to the plane of the body, or death, was considered lack of protection. The time points from 15 to 300 minutes (0.25 to 5 hours) provided a profile of the anticonvulsant activity and potency of each compound and minimized the likelihood of failing to identify slowly absorbed compounds or those with possible anticonvulsant activity in a metabolite. Animals were immediately sacrificed by cervical dislocation either 10 seconds after the appearance of convulsions or 30 seconds post MES, whichever came first. Protection against convulsions were recorded as a quantal (all or none) response.
  • Dose-response curves for orally administered diltiazem, TA-3090, and phenytoin were generated following the establishment of the time course of their anticonvulsant activity. Each compound was prepared in normal saline and administered at the required dose by oral gavage. Sixty minutes later, seizures were induced in the mouse by MES, as in Example 1, and the appearance or inhibition of THE noted.
  • Fig. 2 The time course for protection against MES-induced seizures by orally administered diltiazem and TA-3090 are shown in Fig. 2 and Table IV. Also shown are the protective activities of saline and phenytoin administered as negative and positive control compounds, respectively. Each time point in Fig. 2 represents the percentage of animals protected from tonic seizures, calculated from the data in Table IV, at each time point. Five to 10 animals were tested at each time.
  • both diltiazem (200 mg/kg) and TA-3090 (30 mg/kg) protected mice from seizure in a time dependent fashion.
  • the protective effects of both compounds were maximal at 60 minutes post oral administration, with diltiazem being 100% effective and TA-3090 being 90% effective in protecting against THE in the MES test of epilepsy.
  • diltiazem and TA-3090 exhibited 60% and 80% protection, respectively.
  • diltiazem and TA-3090 still exhibited 43% and 20% protection, respectively.
  • Saline as expected, was ineffective as an anticonvulsant.
  • Table V and Fig. 3 demonstrate that both diltiazem and TA-3090 were effective in preventing generalized tonic-clonic seizures in a concentration dependent manner after oral administration.
  • Probit analysis of the data revealed ED50 values of 29, 9.8, and 3.7 mg/kg for dilitazem, TA-3090, and phenytoin, respectively.
  • both diltiazem and TA-3090 were as effective as phenytoin in their ability to protect against MES-induced seizures, although neither diltiazem or TA-3090 were as potent as phenytoin.
  • This Example shows the efficacy of various metabolites of diltiazem and TA-3090 in inhibiting seizures induced by maximal electroshock (MES) in mice.
  • MA N-monomethyldiltiazem
  • M1 desacetytldiltiazem
  • M3 desacetytldiltiazem
  • mice Male Swiss Webster mice weighing 20-30 grams were obtained from Sasco Inc. (Omaha, Iowa). Animals were housed 5 to a cage for at least one week prior to the study, with food and water ad libitum. Mice were randomly divided into 7 groups, weighed, and treated as follows:
  • Test compounds were administered to groups of 9-20 animals. The dose at which 50% of the total number of animals tested were protected (ED50) was expressed in mg/kg. The ED50 dose was obtained by probit analysis.
  • the metabolite M1, diltiazem and TA-3090 each protected the treated mice from seizures in a dose dependent fashion, with the order of potency being TA-3090 > diltiazem > M1.
  • TA-3090 > diltiazem > M1.
  • M1 at a dose of 300 mg/kg i.p., produced 90% protection, while TA-3090 afforded 90% protection at a dose of 30 mg/kg i.p.
  • Phenytoin showed complete protection from seizure at a dose of 100 mg/kg i.p.
  • ED50 values 31.06 mg/kg, 10.96 mg/kg, and 0.84 mg/kg for M1, diltiazem, and TA-3090, respectively.
  • M1 was approximately three times less potent than phenytoin, but was still able to provide 90% protection.
  • the metabolites MA and MB3 were only 10% effective at the highest concentrations tested. MA, however, possessed definite toxic central nervous system actions as evidenced by extreme lethargy and abnormal postural positioning of all 10 animals receiving the highest dose (300 mg/kg) as well as the death of 5 animals within 10 minutes of drug administration. Animals treated with the highest dose of MB3 (100 mg/kg) were visibly sedated.
  • CSF cerebrospinal fluid

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  1. Verwendung einer Verbindung der Formel
    Figure imgb0005
     in der X ein Wasserstoffatom, einen geradkettigen oder verzweigten Alkylrest mit bis zu 8 Kohlenstoffatomen, eine Hydroxylgruppe, ein Halogenatom oder einen geradkettigen oder verzweigten Alkylhalogenidrest mit bis zu 8 Kohlenstoffatomen bedeutet; Y einen geradkettigen oder verzweigten Alkylenrest mit bis zu 8 Kohlenstoffatomen bedeutet; R₁ ein Wasserstoffatom, eine Hydroxylgruppe oder eine Acetyloxygruppe darstellt; R₂ und R₃ jeweils einen geradkettigen oder verzweigten Alkylrest mit bis zu 8 Kohlenstoffatomen oder einen nicht-aromatischen Cycloalkylrest mit nicht mehr als 6 Kohlenstoffatomen darstellen, oder zusammengenommen einen einzelnen Ring mit nicht mehr als 6 Kohlenstoffatomen bilden, oder deren pharmazeutisch verträgliches Salz zur Herstellung eines Arzneimittels zur Verwendung bei der Behandlung von generalisierten epileptischen Anfallen vom tonisch-clonischen Typ bei Säugern.
  2. Verwendung nach Anspruch 1, wobei X ein Wasserstoffatom oder ein Chloratom in 8-Stellung bedeutet, Y eine Ethylgruppe darstellt, R₁ eine Acetyloxygruppe bedeutet und R₂ und R₃ jeweils Alkylreste darstellen.
  3. Verwendung nach Anspruch 2, wobei R₂ und R₃ jeweils Methylgruppen bedeuten.
  4. Verwendung nach Anspruch 1, wobei die Verbindung (+)(2S,3S)-3-Acetyloxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-on ist.
  5. Verwendung nach Anspruch 1, wobei die Verbindung (+)(2S,3S)-3-Acetyloxy-8-chlor-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-on ist.
  6. Verwendung nach einem der vorangehenden Ansprüche, wobei das Arzneimittel zur oralen Verabreichung vorgesehen ist.
  7. Verwendung nach Anspruch 6, wobei das Arzneimittel in einer geteilten Dosierungsform 3 bis 4 mal täglich verabreicht wird, wobei eine Gesamtdosis von 0,5 bis 360 mg/Tag bereitgestellt wird.
  8. Verwendung nach einem der Ansprüche 1 bis 5, wobei das Arzneimittel zur Verabreichung durch Injektion vorgesehen ist.
EP89906896A 1988-05-24 1989-05-23 Benzothiazepine zur Herstellung von Medikamenten zur Milderung von epileptischen Anfällen Expired - Lifetime EP0368994B1 (de)

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US07/198,054 US4879289A (en) 1988-05-24 1988-05-24 Method of ameliorating epileptic seizures
US198054 1988-05-24

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US4963545A (en) * 1988-05-24 1990-10-16 Marion Laboratories, Inc. Benzothiazepine anti-seizure method
US4879289A (en) * 1988-05-24 1989-11-07 Marion Laboratories, Inc. Method of ameliorating epileptic seizures
US5002773A (en) * 1989-09-29 1991-03-26 Marion Merrell Dow Inc. Transdermal delivery of (+) (2S,3S)-3-acetoxy-8-chloro-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one
US5023355A (en) * 1990-06-20 1991-06-11 Globus Alfred R Stabilized B-carotene
CA2061353A1 (en) * 1991-02-26 1992-08-27 Sakae Murata Prophylactic and curing agent for sequelae of cerebral neurocyte dyscrasia
US5378698A (en) * 1991-10-21 1995-01-03 Shionogi & Co., Ltd. Benzothiazepine derivatives
US6635277B2 (en) 2000-04-12 2003-10-21 Wockhardt Limited Composition for pulsatile delivery of diltiazem and process of manufacture
CA2585876A1 (en) * 2003-11-06 2005-05-26 Grace Laboratories, Inc. Immunosorbent tests for assessing paroxysmal cerebral discharges
US20100029613A1 (en) * 2004-11-15 2010-02-04 University Of Rochester Treatment and prevention of epilepsy

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US3075967A (en) * 1961-06-12 1963-01-29 Olin Mathieson Benzothiazines
US3562257A (en) * 1967-10-28 1971-02-09 Tanabe Seiyaku Co Benzothiazepine derivatives
US3895006A (en) * 1974-04-19 1975-07-15 Squibb & Sons Inc 5-(Substituted amino)alkyl)-2-aryl-3-halo-1,5-benzothiazepin-4(5H)-ones
US3983106A (en) * 1975-07-03 1976-09-28 E. R. Squibb & Sons, Inc. 5-Heterocyclicalkyl-2-aryl-3-halo 1,5-benzothiazepin-4(5H)-ones
JPS59144776A (ja) * 1983-02-04 1984-08-18 Tokawa Tetsuo ベンゾチアゼピン誘導体の光学分割法
US4567175A (en) * 1983-06-03 1986-01-28 Tanabe Seiyaku Co., Ltd. 8-Chloro-1,5-benzothiazepine derivatives
JPS60146884A (ja) * 1984-01-09 1985-08-02 Nippon Chem:Kk １，５ベンゾチアゼピン誘導体の製造法
US4885375A (en) * 1988-05-18 1989-12-05 Marion Laboratories, Inc. Resolution of 3-(4-methoxyphenyl)glycidic acid with in situ conversion to alkyl esters
US4879289A (en) * 1988-05-24 1989-11-07 Marion Laboratories, Inc. Method of ameliorating epileptic seizures

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AU606531B2 (en) 1991-02-07
IL90397A0 (en) 1990-01-18
AU3760189A (en) 1989-12-12
JPH0623105B2 (ja) 1994-03-30
US4879289A (en) 1989-11-07
DE68911273T2 (de) 1994-03-31
IL90397A (en) 1993-05-13
EP0368994A1 (de) 1990-05-23
WO1989011281A1 (en) 1989-11-30
JPH02502920A (ja) 1990-09-13
DE68911273D1 (de) 1994-01-20
CA1317593C (en) 1993-05-11
USRE35095E (en) 1995-11-21
EP0368994A4 (en) 1991-11-21

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